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The GABA_A agonist muscimol attenuates induced airway constriction in guinea pigs in vivo

¹Department of Anesthesiology, ²Division of Critical Care, College of Physicians and Surgeons, Columbia University, New York, New York

Submitted 2 October 2008 ; accepted in final form 11 February 2009

GABA_A channels are ubiquitously expressed on neuronal cells and act via an inward chloride current to hyperpolarize the cell membrane of mature neurons. Expression and function of GABA_A channels on airway smooth muscle cells has been demonstrated in vitro. Airway smooth muscle cell membrane hyperpolarization contributes to relaxation. We hypothesized that muscimol, a selective GABA_A agonist, could act on endogenous GABA_A channels expressed on airway smooth muscle to attenuate induced increases in airway pressures in anesthetized guinea pigs in vivo. In an effort to localize muscimol's effect to GABA_A channels expressed on airway smooth muscle, we pretreated guinea pigs with a selective GABA_A antagonist (gabazine) or eliminated lung neural control from central parasympathetic, sympathetic, and nonadrenergic, noncholinergic (NANC) nerves before muscimol treatment. Pretreatment with intravenous muscimol alone attenuated intravenous histamine-, intravenous acetylcholine-, or vagal nerve-stimulated increases in peak pulmonary inflation pressure. Pretreatment with the GABA_A antagonist gabazine blocked muscimol's effect. After the elimination of neural input to airway tone by central parasympathetic nerves, peripheral sympathetic nerves, and NANC nerves, intravenous muscimol retained its ability to block intravenous acetylcholine-induced increases in peak pulmonary inflation pressures. These findings demonstrate that the GABA_A agonist muscimol acting specifically via GABA_A channel activation attenuates airway constriction independently of neural contributions. These findings suggest that therapeutics directed at the airway smooth muscle GABA_A channel may be a novel therapy for airway constriction following airway irritation and possibly more broadly in diseases such as asthma and chronic obstructive pulmonary disease.

acetylcholine; histamine; vagal nerve stimulation; gabazine; guanethidine